This application addresses the Broad Challenge Area (15): Translational Science and specific Challenge Topic, 15-DK-111, the role of gastrointestinal surgical procedures in amelioration of type 2 diabetes. With the increased prevalence to type-2 diabetes mellitus (T2DM), new strategies for diabetes prevention are needed. We have developed and characterized a novel rat model of T2DM, the University of California, Davis T2DM (UCD-T2DM) rat, which more accurately models the pathophysiology of clinical human T2DM than other available models. The IT surgical model is of interest because it isolates one of the major anatomic alterations performed in Roux-en-Y gastric bypass (RYGB), namely IT surgery moves the distal small intestine proximally, resulting in increased contact of less completely digested nutrients with the mucosa of the distal small intestine resulting in increased secretion of gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide-YY (PYY). In comparison, RYGB reduces gastric volume, bypasses the proximal small intestine and increases the nutrient flux to the distal small intestine. In our current studies, we have demonstrated improved glucose tolerance and insulin sensitivity and a significant (~3 month) delay in the age of diabetes onset in IT compared with sham-operated animals, as well as increases of circulating active GLP-1 and PYY. Thus, we are proposing to further investigate potential mechanisms by which IT surgery delays diabetes. Such studies are likely to help identify new non-surgical approaches for the prevention and treatment of insulin resistance and T2DM. We are proposing the following Specific Aims: 1: To test the hypothesis that IT surgery in pre-diabetic UCD-T2DM rats delays the onset of T2DM by influencing the production, secretion, and signaling of GI hormones (GLP-1, PYY, and ghrelin), and the adipocyte hormone, adiponectin and by altering bile acid metabolism and intestinal microflora. To this end, blood glucose will be monitored and in vivo assessment of glucose tolerance and insulin sensitivity will be measured. Monthly measurements of circulating lipids, hormones and bile acids will be taken. Ileal and cecal microbial profiling and specific tissue analysis of ectopic lipid deposition, islet morphology and anorexegenic and orexegenic hormone receptor gene expression at different levels of the gut-brain axis will be performed. 2: To test the hypothesis that IT surgery delays the onset of diabetes by preserving mitochondrial function which deteriorates during the development and progression of T2DM. To this end, mitochondrial function (oxygen uptake, ROS production, mitochondrial coupling, and calcium transport) will be evaluated in mitochondria isolated from several tissues (liver, skeletal muscle, heart, and adipose). All tissue analyses will be performed at 1 and 3 months after surgery in IT, Sham and non-surgical control groups. PUBLIC HEALTH RELEVANCE: The clinical observation that bariatric surgery reverses T2DM provides researchers with a new tool for the identification of new prevention and treatment options for T2DM. Thus, the development and utilization of animal models for investigating the mechanisms by which bariatric surgical procedures ameliorate diabetes are urgently needed. Recent results from our laboratory have demonstrated that ileal interposition surgery significantly delays T2DM onset in a novel rat model developed in our laboratory, the UCD-T2DM rat, which more accurately models clinical human T2DM than other available rodent models. Thus, the major goal of the proposed study is to investigate several potential mechanisms by which ileal interposition surgery improves insulin sensitivity and glucose tolerance and delays the onset of T2DM in UCD-T2DM rats. The contributions of alterations in the production of gastrointestinal and adipocyte hormones, changes of bile acids and intestinal microbial composition, as well as mitochondrial function will be assessed.